Download Immune Strategies to Infection

Immune Strategies to Infection
Infection and innate immunity (Abbas pp 26)
The innate immune response involves a variety of protective/effective mechanisms
including:
 Epithelial barriers offering physical and mechanical barriers
 Chemical factors: in response to microbes, macrophages and other cells
secrete cytokines that mediate many of the cellular reactions of innate
immunity (i.e.: inflammatory cytokines  IL1, IL6, IL8, IL12, TNF-a). These
activate vascular endothelium, lymphocytes, chemotactic factor & acute phase
protein production. This causes chemoattraction of lymphocytes site of
infections.
 Natural killer cells go to site of infection and kill intracellular microbes by
killing the infected cell.
 Phagocytes such as: neutrophils, basophils, eosinophils, macrophages all play
a role in recognising and ingesting microbes for intracellular killing.
 Complement pathway: these are membrane associated proteins (proteolytic
enzymes) that play three major roles: 1) opsonisation (C3b), 2) breakdown
products act as chemoattractants, 3) forms MAC that punches holes in
microbial cell membrane.
These mechanisms provide an effective strategy against microbial infections, but they
do not provide long last immunity nor memory. These mechanisms are immediate and
control the infection while the adaptive response is being formed.
Infection and specific immunity (Abbas Chapter 6 & 8)
If the infection reaches a threshold level (i.e.: virulence is high, and dose is high) and
eludes the innate arm of the immune response, then adaptive immunity is activated.
This occurs as a result of antigen presentation to naïve T cells at the lymph nodes,
which get activated and then travel to the site of infection to elicit a response (cell
mediated), or antigen may remain in the lymph nodes, activating B cells for antibody
production (humoral). What determines whether a T or B cell response is initiated?
That depends on the type of cytokines produced by the innate immune response.
What happens after a person is infected with a microbe? Refer to lecture notes for the
different phases and stages that can occur in eradicating the infection.
Stages/Phases of infections
The innate response occurs within 0-4 hours, where preformed mediators are
released, this recruits and activates the effector cells (i.e.: NK, phagocytes,
complement, acute phase proteins etc) – as a result – these results migrate to the site
of infection in an activated form and remove the infectious agent. After this (4-96
hrs) – if the infection is still present, then more recruitment of inflammatory cells
occurs and more chemical mediators are secreted. These cells recognise the infectious
agent and get activated – and as a result increased inflammation results and the
infectious agent is removed. After 96 hours, the antigen may make its way (i.e.:
APCs present it to them) to the lymph nodes. It is then recognised by naïve T cells,
which are activated after the following occurs: T cells recognise ligands on APCs,
TCR recognises MHC-associated peptide antigens, CD4/CD8 co receptors recognise
MHC molecules, adhesion molecules strengthen binding of T cells to APCs,
costimulation provided by APCs. This cause’s clonal expansion, where T
lymphocytes begin to proliferate + differentiate, resulting in expansion of antigen
specific clones. CD4+ helper T cells may differentiate into effector cells that secrete
cytokines mainly to activate macrophages and B lymphocytes & CD8+ T cells may
differentiate into CTLs that kill infected cells expressing the antigen. This results in
removal of infectious agent. But memory is preserved after this. So in the event of a
re-infection, preformed antibody and memory T cells recognise the antigen – rapid
expansion and differentiation into effector cells occurs – together they remove the
infectious agent.
Pathogens can be found in various compartments (Notes)
Infections can be intracellular or extracellular. Intracellular infections can be within
the cytoplasm or within vesicles, which are located in the cytoplasm. Examples of the
former: viruses, Chlamydia, rickettsia, listeria etc. Examples of the latter:
mycobacteria, salmonella, listeria, Legionella etc. How does the body control the
infections within the cytoplasm? This is done mainly via CD8 T cell activation and
differentiation into CTLs that directly kill the infected cell, NK cells that respond by
directly killing the infected cells as well. How does the body control the infections
that are within vesicles? T cells recognise these cells and then kill them, CD4+ cells
get activated and produce cytokines that activate macrophages and B cells (which
produce antibodies and kill infected cell). NK cells kill the infected cell but also
produce a macrophage activating cytokine – IFN-γ.
Extracellular infections can occur in interstitial places, blood, and lymph. Some
examples of pathogens that do this are: viruses, protozoa, fungi, Helminths, bacteria
etc. The main way the immune response reacts to this sort of infection is by humoral
immunity (antibody protection), phagocytosis and neutralisation. Extracellular
infections can also occur within epithelial surfaces. Many examples of microbes cause
this (i.e.: candida, strep, staph etc). Ig A antibodies are produced in immunity, and
inflammatory cells are recruited to the site of infiltration.
Immunity to bacteria (Abbas pp 109)
Bacteria can be gram +ve or gram –ve. Gram +ve bacteria are opsonised and
phagocytosed. Gram –ve bacteria are opsonised and undergo lysis by the complement
mechanism. Intracellular bacteria are killed by macrophage activation by T cell
derived cytokines, and also CTLs directly killing the infected cell. If the bacteria is
non-invasive, then a humoral response (antibody production) is enough to neutralise
the toxin.
Antibody
Humoral immunity is mediated by antibodies. Antibodies prevent infection by
blocking the ability of microbes to invade host cells. These can be done by interfering
with the microbe’s ability to attach to the host tissues. Antibodies have the following
functions: neutralise infectivity and pathogenicity of toxins by binding to them and
interfering with their functions, opsonise microbes therefore promoting phagocytosis,
activate the classical complement pathway (stimulate inflammation / MAC). The
alternate pathway does not require antibody to be activated (immediate response).
Extracellular bacteria
Extracellular bacteria are first (0-4hrs) handled by the innate immune response.
Macrophages and other cells secrete cytokines and chemokines that attract
inflammatory cells to the site of infection. Alternate complement pathway is
activated. This causes an immediate inflammatory response which keeps the bacteria
in check before other processes take over. The adaptive immune response takes over,
and this involves antibody production due to B cell activation  plasma cells, and
cytokines released due to CD4+ T cells activated + CTLS from CD8+ T cells being
activated. The antibodies produce further induce classical complement pathway
activation. Therefore together they attack the bacteria.
Intracellular bacteria
Cell mediated immune response take control of this type of bacteria. The bacteria can
be located within vesicles in cells, or within the cytoplasm itself. Intracellular bacteria
residing in vesicles within phagocytes are removed by activated phagocytes. This
activation is provided by CD4+ T cells, production of cytokines etc. CD8+ T cells on
the other hand differentiate into CTLs and directly kill the infected cell (bacteria
within cytoplasm of cell) thus eliminating the infection.
The innate immunity prevails again initially, with the activation of macrophages and
inflammatory cells.
Immunity to fungi
For elimination of fungi, the innate arm of the immune response is more efficient. The
innate response involves: chemotactic factors, chemokines and other chemicals that
lure inflammatory cells to the site of infection, macrophages erode the infection.
Adaptive immunity is complex. T cells get activated, and secrete macrophage
activating cytokines, activated macrophages phagocytose the fungal infection.
Meanwhile, differentiated B cells produce antibodies to fungal toxins. Spores
produced by fungi bind to IgE – this degranulates the mast cell – histamine is
released. Histamine vasodilates vessels, increase fluid flow – wash out spores.
Immunity to protozoa and Helminths
For most of these intracellular infections – the immune response is not efficient
enough to eliminate the infection totally – but only achieves this partially. Thus,
infection is controlled not eliminated. Innate immunity is useless, so adaptive
immunity is of paramount importance.
Protozoans
Antibody acts as an opsonising agent, so that phagocytosis can occur. CD4+ T cells
secrete cytokines activating macrophages and B cells. CD8+ T cells differentiate to
CTLs and produce cytotoxic T cell effects. Th1 cytokines deal with intracellular
parasites whilst TNF-a controls parasitic infection, but can be harmful when produced
in large amounts. Granulomas formed to wall off infection – prevent spread.
Helminths
Antibody is very important here, i.e.: IgA inhibits attachment, IgG serves as an
opsonin. For tissue parasites, complement fixation via IgA and IgM important (i.e.:
they activate complement pathway). IgE causes mast cell degranulation – this
increases fluid flow and expulse Helminths from GIT. Eosinophils accumulate at site
of infection – mediate ADCC (antigen dependent cellular cytotoxicity).
Immune escape mechanisms (Abbas pp 122)
Bacteria
Bacteria can vary their antigenic material known as antigenic variation – i.e.: E.coli.
Avoidance of complement mediated damage: 1) outer capsule of microbe not
penetrable 2) outer surface configuration does not allow C3b binding, 3) diversionary
structures (decoy cytokine receptors, or antibody binding to diversionary structure
doesn’t do anything), 4) produce enzymes that degrade complement products, 5)
resistance to MAC forming + inserting, 6) secreting decoy proteins so complement
binding is diverted from binding to bacteria.
Resistance to phagocytosis: 1) phagocytosis requires chemotaxis, but toxins
repel/prevent chemotaxis therefore phagocytes don’t come near infection, 2) bacteria
may have outer coats that inhibits phagocytosis (i.e.: Pneumococcus), 3) inhibit
phagolysosome fusion and escape from vesicles of phagocytes into cytosol.
Viruses
Antigenic drift (influenza), blocking complement system (i.e.: HSV produces C3b
binding protein and augments decay of C3bBb), immunosuppressive cytokines
(Epstein Barr virus), cytokine receptor homologue (Vaccinia, CMV), inhibits antigen
processing pathway (i.e.: CMV), infects immune cells.
Parasites
Sequestered in a particular anatomical position so difficult access, avoids
phagocytosis, antigenic variation – avoids recognition, it somehow has same surface
antigens of host so immune system thinks its also part of host, suppresses immune
system, lymphocytoxic factor, release spores that can mop up any antibody.